A Spatial and Temporal Gradient of Fgf Differentially Regulates Distinct Stages of Neural Development in the Zebrafish Inner Ear

Abstract

Neuroblasts of the statoacoustic ganglion (SAG) initially form in the floor of the otic vesicle during a relatively brief developmental window. They soon delaminate and undergo a protracted phase of proliferation and migration (transit-amplification). Neuroblasts eventually differentiate and extend processes bi-directionally to synapse with hair cells in the inner ear and various targets in the hindbrain. Our studies in zebrafish have shown that Fgf signaling controls multiple phases of this complex developmental process. Moderate levels of Fgf in a gradient emanating from the nascent utricular macula specify SAG neuroblasts in laterally adjacent otic epithelium. At a later stage, differentiating SAG neurons express Fgf5, which serves two functions: First, as SAG neurons accumulate, increasing levels of Fgf exceed an upper threshold that terminates the initial phase of neuroblast specification. Second, elevated Fgf delays differentiation of transit-amplifying cells, balancing the rate of progenitor renewal with neuronal differentiation. Laser-ablation of mature SAG neurons abolishes feedback-inhibition and causes precocious neuronal differentiation. Similar effects are obtained by Fgf5-knockdown or global impairment of Fgf signaling, whereas Fgf misexpression has the opposite effect. Thus Fgf signaling renders SAG development self-regulating, ensuring steady production of an appropriate number of neurons as the larva grows.

Spemann organizer gene Goosecoid promotes delamination of neuroblasts from the otic vesicle

“…Initially, a subset of the cells in the otic epithelium is specified for neural fate by the up-regulation of the proneural gene neurogenin1 (ngn1) (1,2). Otic expression of ngn1 is first detected by 16 hpf, peaks at around 24 hours postfertilization (hpf), and then gradually declines, ceasing entirely by 42 hpf (3). Throughout this period, a subset of newly specified neuroblasts undergoes epithelial-to-mesenchymal transition (EMT) and delaminates from the otic vesicle (4)(5)(6).…”

“…In zebrafish, most neuroblasts lose ngn1 expression after leaving the otic vesicle and subsequently up-regulate the related proneural factor neurod (7,8). neurod-expressing cells form a group of proliferating and migrating precursors called the transit-amplifying (TA) pool (3,9). As TA cells differentiate into mature SAG neurons, they lose neurod expression and upregulate mature neuronal markers such as Islet1 and Islet2b (10,11).…”

“…As TA cells differentiate into mature SAG neurons, they lose neurod expression and upregulate mature neuronal markers such as Islet1 and Islet2b (10,11). The first mature Isl1+ SAG neurons are detected by 20 hpf and subsequently accumulate at a linear rate through at least 72 hpf (3). At the same time, the TA pool is maintained as a stable population by proliferative renewal, assuring further growth of the SAG as larvae develop (3).…”

“…The first mature Isl1+ SAG neurons are detected by 20 hpf and subsequently accumulate at a linear rate through at least 72 hpf (3). At the same time, the TA pool is maintained as a stable population by proliferative renewal, assuring further growth of the SAG as larvae develop (3).…”

“…Specification of the neurogenic domain is established by a low threshold level of Fgf signaling (3,12). However, nothing is known about the mechanisms regulating delamination of neuroblasts from the otic vesicle.…”